Mycobacteriology Laboratory

Micobatteriologia

Referents: Prof. Maria Rosalia Pasca (Full Professor), Giulia Degiacomi (RTD-B)

Co-workers: Deborah Recchia (Post-doc), Alessandro Stamilla (Post-doc)

 

1. Research for new antitubercular drugs and study of their mechanism of action and resistance Tuberculosis (TB) remains the leading cause of mortality due to a single bacterial agent, Mycobacterium tuberculosis. TB caused by M. tuberculosis multi-drug resistant strains (MDR and XDR) is a major threat to public health worldwide. There is therefore an urgent need for new antitubercular drugs, which can counteract the drug resistance. The research activity of the Mycobacteriology Laboratory has focused on the development of new compounds with antitubercular activity in the early drug discovery phases, using innovative in vitro approaches for the identification and characterization of their mechanism of action and resistance. Furthermore, the identification and validation of cellular targets is fundamental in the study of the mechanism of action of antitubercular compounds. Thanks to gene regulation systems designed specifically for application in M. tuberculosis, it is possible to construct conditional mutants that can also be used in the drug discovery process. The Mycobacteriology Laboratory has identified the cellular target of benzothiazinones, which are currently in phase II of human clinical trials (Macozinone, BTZ043). Thanks also to collaborations undertaken during previous projects funded by the European Commission, we are studying the mechanism of action of new compounds active against M. tuberculosis and we are validating novel cellular targets of the pathogen.

Collaborations:

  • Makarov V (Russian Academy of Science, Moscow, Russia);
  • Mikusova K (Comenius University, Bratislava, Slovakia);
  • Baltas M (CNRS, Toulouse, France);
  • Lherbet C (Paul Sabatier-Toulouse III University, Toulouse, France);
  • Manetti F (Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Italy).

 

2. European Regimen Accelerator For Tuberculosis (ERA4TB; IMI 2 - Horizon 2020) The Mycobacteriology Laboratory is one of the 31 partners of the project funded by the European Commission "European Regimen Accelerator For Tuberculosis" (ERA4TB; IMI 2 - Horizon 2020; 1 January 2020 - 31 December 2025), which has a duration of six years. The aim of this project is to develop at least two new drug combination regimens ready for Phase II clinical evaluation (https://era4tb.org/). We are characterizing the mechanism of action of 4 antitubercular compounds, 3 of which are already in Phase I of clinical trials. We are also developing an in vitro model of granuloma formation that will allow us to test the activity of compounds in this phase of M. tuberculosis infection.

Collaborations:

  • Cole ST (Pasteur Institute, Paris, France);
  • Ramon-Garcia S (University of Zaragoza, Spain);
  • Manganelli R (Department of Molecular Medicine, University of Padua, Italy).

 

3. New weapons against Mycobacterium abscessus (Italian Cystic Fibrosis Research Foundation: FFC # 19/2018; FFC # 14/2020; FFC # 18/2021) Recently, the Mycobacteriology Laboratory, thanks to its long experience in TB field, has opened a new research line aimed at studying non-tuberculous mycobacteria (NTM), in particular Mycobacterium abscesssus. NTM are emerging as important pathogens among cystic fibrosis (CF) patients worldwide (3.3-22.6%). Among these, M. abscessus is the most common pathogen in CF centers around the world. Current drug therapy against M. abscessus can last up to 2 years and its failure causes a rapid decline in lung function. M. abscessus is intrinsically resistant to many drugs, so, there is an urgent need for new and effective drugs against this pathogen with a novel mechanism of action. Thanks to the projects founded by the Italian Cystic Fibrosis Research Foundation (FFC # 19/2018; FFC # 14/2020; FFC # 18/2021), we are testing new classes of compounds against M. abscessus growth. In particular, out of over than 700 compounds we selected only one molecule active in vitro and in vivo against this emerging pathogen. The study of its mechanism of action is ongoing. We have also shown that mefloquine, an antimalarial drug, is also active against M. abscessus, inhibiting the mycolic acid metabolism. Furthermore, we are testing new classes of compounds against M. abscessus growth, of which if active, we will study the mechanism of action.

Collaborations:

  • Makarov V (Russian Academy of Science, Moscow, Russia);
  • Ramon-Garcia S (University of Zaragoza, Spain);
  • Cirillo D (San Raffaele Hospital, Milan, Italy).

 

4. New strategies against intracellular mycobacteria (MUR-PRIN 2020) This project studies the host-pathogen interaction with the aim of designing an innovative strategy to permanently eradicate M. abscessus and M. tuberculosis using a multidisciplinary approach. The Mycobacteriology Laboratory will contribute to the study of host-pathogen interaction in order to decipher new precision nanomedicine tools.

Collaborations:

  • Rizzello L (Department of Pharmaceutical Sciences, University of Milan, Italy);
  • Manganelli R (Department of Molecular Medicine, University of Padua, Italy).